It’s in your genes, or is it? The genetics of autoinflammatory diseases

Autoinflammatory diseases have a variety of causes. Some are clearly genetic–they are caused by single mutations in specific genes. These abnormal genes produce abnormal proteins that cause unprovoked episodes of inflammation. If you have the abnormal gene (for the most part) you develop the disease. If you don’t have the gene, you don’t develop the disease. Familial Mediterranean Fever (MEFV), cryopyrin associated periodic syndrome (NLRP3), and the TNF-receptor associated periodic syndrome (TNFRSF1A), are examples of autoinflammatory diseases associated with mutations in single genes. These diseases are often called hereditary periodic fever syndromes, although they are not always “hereditary” (passed down from parent to child); many are caused by new mutations that arise in the embryo.

Some types of autoinflammatory diseases have associations with specific genes, such as Behcet’s disease with the gene HLA-B51. Behcet’s is characterized by recurrent oral and genital ulcers, rash, and episodes of eye inflammation (uveitis). Unlike the genetic diseases above, having the gene HLA-B51 is not sufficient to have the disease. This complex disease is likely caused by interplay between HLA-B51, other genes, and the environment (it is interesting to note that patients with Behcet’s that live in the Middle East have a more severe disease than patients with Behcet’s that live in the United States).

Finally, some autoinflammatory diseases do not appear to be associated with any specific gene. PFAPA (periodic fevers, aphthous stomatitis, pharyngitis, and adenitits), is such an example. This is an autoinflammatory disease that commonly affects children, and it is characterized by periodic episodes of fever and the associated symptoms that give it its name. To date, no specific gene has been associated with the development of this disease. The fact that removal of the tonsils appears to be curative for many patients suggests that perhaps an infection that resides in the tonsils contributes to the expression of this disease.

We are still just beginning to understand the causes of these fascinating autoinflammatory diseases. It is still unclear what makes patients with the same genetic mutation have mild or severe disease. We also don’t know how the environment plays a role in the expression of this disease. Further research over the next few years should be able to give us better answers to these important questions.

To review the wide variety of autoinflammatory syndromes (and their specific causes), please refer to this comparison chart by the Autoinflammatory Alliance, by far the most complete chart of autoinflammatory diseases I’ve seen.

Adult-onset Still’s Disease (AOSD) is an interesting disease. In general, it can present in one of three ways.
-About a third of patients have one acute episode of AOSD (fevers, rash, elevation in inflammatory markers, arthritis) which may last several months, but which then completely resolves, never to return.
-Another third of patients can have several episodes of AOSD throughout their lifetime (sometimes spread out over years), while being completely symptom-free and without needing medications in between.
-Finally, a third of patients develop a more chronic disease with continuous fever or arthritis. These patients require daily medications to maintain the disease under control.

However, patients with other rheumatologic diseases, including rheumatoid arthritis (RA) and lupus, can develop a syndrome which looks very much like AOSD and is called macrophage activation syndrome (MAS). This disease is thought to be caused by an immune system that can’t shut itself off. For unclear reasons, the body begins to produce a lot of inflammatory molecules, white blood cells multiply uncontrollably in various tissues in the body, and these changes cause a very severe disease that looks very much like AOSD. The treatment for AOSD and MAS are generally the same and involve steroids and newer biologic medications (IL-1 and IL-6 inhibitors).

For you, it is interesting to speculate whether you had the more chronic AOSD all along, or whether you had RA and developed an episode of MAS on top. I hope you’re now better!